Long-Term Safety Evaluation of Continuous Intraocular Delivery of Aflibercept by the Intravitreal Gene Therapy Candidate ADVM-022 in Nonhuman Primates

Kiss, Szilárd; Bender, Kristina Oresic; Grishanin, Ruslan N.; Hanna, Kelly; Nieves, Julio; Sharma, Pallavi; Nguyen, Aivan; Rosario, Romeo; Greengard, Judith S.; Gelfman, Claire M.; Gasmi, Mehdi

doi:10.1167/tvst.10.1.34

Cited by 26 publications

(28 citation statements)

References 39 publications

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“…Importantly, in those patients who consented for aqueous taps in the OPTIC trial, there was sustained long-term aflibercept protein expression, out to 104 weeks in one patient. With the exception of one patient who required rescue injections, all aflibercept protein levels expressed as a result of ADVM-022 gene therapy were found to be in therapeutic range when compared to the commercially available Eylea (aflibercept recombinant protein, Regeneron Pharmaceuticals) injection [30,32,35].…”

Section: Retinal Gene Therapies Voretigene Neporvovec-rzyl (Luxturna)mentioning

confidence: 89%

“…1). With ADVM-022, the need for repeated intravitreal injections every 4-8 weeks can be mitigated with a resulting decrease in treatment burden [30].…”

Section: Retinal Gene Therapies Voretigene Neporvovec-rzyl (Luxturna)mentioning

confidence: 99%

“…Nonhuman primate studies with ADVM-022 have found that a single intravitreal injection of ADVM-022 resulted in sustained expression of aflibercept for 30 months [30]. Moreover, the aflibercept was able to inhibit choroidal neovascularization in a nonhuman primate model of nAMD, even when injected 13months prior to lasering [31].…”

Section: Retinal Gene Therapies Voretigene Neporvovec-rzyl (Luxturna)mentioning

confidence: 99%

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Review of gene therapies for age-related macular degeneration

Khanani

Thomas

Aziz

et al. 2022

Eye

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Gene therapies aim to deliver a therapeutic payload to specified tissues with underlying protein deficiency. Since the 1990s, gene therapies have been explored as potential treatments for chronic conditions requiring lifetime care and medical management. Ocular gene therapies target a range of ocular disorders, but retinal diseases are of particular importance due to the prevalence of retinal disease and the current treatment burden of such diseases on affected patients, as well as the challenge of properly delivering these therapies to the target tissue. The purpose of this review is to provide an update on the most current data available for five different retinal gene therapies currently undergoing clinical trials for use against age-related macular degeneration (AMD) and the development of novel delivery routes for the administration of such therapies. Research has been performed and compiled from PubMed and the select authors of this manuscript on the treatment and effectiveness of five current retinal gene therapies: Luxturna, ADVM-022, RGX-314, GT-005, and HMR59. We present the available data of current clinical trials for the treatment of neovascular and dry age-related macular degeneration with different AAV-based gene therapies. We also present current research on the progress of developing novel routes of administration for ocular gene therapies. Retinal gene therapies offer the potential for life-changing treatment for chronic conditions like age-related macular degeneration with a single administration. In doing so, gene therapies change the landscape of treatment options for these chronic conditions for both patient and provider.

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Section: Retinal Gene Therapies Voretigene Neporvovec-rzyl (Luxturna)mentioning

confidence: 89%

“…1). With ADVM-022, the need for repeated intravitreal injections every 4-8 weeks can be mitigated with a resulting decrease in treatment burden [30].…”

Section: Retinal Gene Therapies Voretigene Neporvovec-rzyl (Luxturna)mentioning

confidence: 99%

Section: Retinal Gene Therapies Voretigene Neporvovec-rzyl (Luxturna)mentioning

confidence: 99%

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Review of gene therapies for age-related macular degeneration

Khanani

Thomas

Aziz

et al. 2022

Eye

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“…All of these agents have high binding affinity to VEGF, and they block the VEGF signaling pathway with high efficiency. 40 However, up to now, only one product (aflibercept) has been vectorized 41,42 and tested in clinical trials for retinal vasculopathy (ClinicalTrials.gov: NCT04418427 and NCT04645212), and none of them have been reported to treat corneal diseases as a vectored transgene for therapy. Our report represents the earliest study to engineer into an AAV vector the clinically proven anti-VEGF drug, conbercept, to treat CoNV.…”

Section: Discussionmentioning

confidence: 99%

Efficacious, safe, and stable inhibition of corneal neovascularization by AAV-vectored anti-VEGF therapeutics

Sun

Tian

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Corneal neovascularization (CoNV) leads to visual impairment, affecting over 1.4 million people in the United States per year. It is caused by a variety of pathologies, such as inflammation, hypoxia, and limbal barrier dysfunction. Injection of the antivascular endothelial growth factor (VEGF) drug KH902 (conbercept) can inhibit CoNV but requires repeated dosing that produces associated side effects, such as cornea scar. To explore more efficacious and long-lasting treatment of CoNV, we employed recombinant adeno-associated virus (rAAV)2 and rAAV8 vectors to mediate KH902 expression via a single intrastromal injection and investigated its anti-angiogenic effects and safety in both alkali-burn-and suture-induced CoNV mouse models. Our results showed that rAAV-mediated KH902 mRNA expression in the cornea was sustained for at least 3 months after a single intrastromal injection. Moreover, the expression level of rAAV8-KH902 far exceeded that of rAAV2-KH902. A single-dose rAAV8-KH902 treatment at 8 Â 10 8 genome copies (GCs) per cornea dramatically inhibited CoNV for an extended period of time in mouse CoNV models without adverse events, whereas the inhibition of CoNV by a single intrastromal administration of the conbercept drug lasted for only 10À14 days. Overall, our study demonstrated that the treatment of CoNV with a single dose of rAAV8-KH902 via intrastromal administration was safe, effective, and long lasting, representing a novel therapeutic strategy for CoNV.

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“…Gene therapy technology is useful for treating genetic defects in humans and horses, − but this raises concerns about gene doping, which is simply the abuse and misuse of gene therapy. The WADA and IFHA define gene doping in their regulations, which include prohibiting the introduction of an exogenous transgene into the body …”

mentioning

confidence: 99%

Robustness of Digital PCR and Real-Time PCR in Transgene Detection for Gene-Doping Control

et al. 2021

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Gene doping is banned in human sports, horseracing, and equestrian sports. One possible form of gene doping is to administer exogenous genes, called transgenes. Several transgene detection methods based on quantitative PCR have been developed. In this study, we investigated the robustness of digital PCR and real-time PCR in transgene detection using primers and probes that matched (P-true) or incompletely matched (P-false) the template DNA. Fluorescence intensity was significantly reduced when substituted probes were used compared to that using the matched probe in both digital and real-time PCR assays. Digital PCR yielded a similar copy number regardless of the probe (P-true: 1230.7, P-false: 1229.7), whereas real-time PCR revealed a decrease in sensitivity based on C q values (P-true: 23.5, P-false: 29.7). When substituted primers were used, the detected copy number decreased in the digital PCR assay, and the C q value in real-time PCR was much higher. Interestingly, digital PCR copy numbers improved by performing PCR at a low annealing temperature, even if a substituted probe was used. Thus, when primer and probe sequences did not completely match the template transgene, digital PCR was relatively robust, but real-time PCR was less sensitive. Although PCR specificity may be reduced, PCR sensitivity can be improved by lowering the annealing temperature. If the target sequence is substituted to escape doping detection, it may be desirable to set the annealing temperature lower and use a more robust method, such as digital PCR, to increase the detection of positive cases, which will also result in fewer false-negative results.

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Long-Term Safety Evaluation of Continuous Intraocular Delivery of Aflibercept by the Intravitreal Gene Therapy Candidate ADVM-022 in Nonhuman Primates

Abstract: Long-term safety evaluation of continuous intraocular delivery of aflibercept by the intravitreal gene therapy candidate ADVM-022 in nonhuman primates.

Cited by 26 publications

References 39 publications

Review of gene therapies for age-related macular degeneration

Review of gene therapies for age-related macular degeneration

Efficacious, safe, and stable inhibition of corneal neovascularization by AAV-vectored anti-VEGF therapeutics

Robustness of Digital PCR and Real-Time PCR in Transgene Detection for Gene-Doping Control

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